Depression and cardiovascular disease: The deep blue sea of women's heart

Abstract Cardiovascular disease (CVD) constitutes a leading worldwide health problem, with increasing evidence of differences between women and men both in epidemiology, pathophysiology, clinical management, and outcomes. Data from the literature suggest that women experience a doubled incidence of CVD related deaths, while angina, heart failure and stroke are increasingly prevalent in females. About 20–25% of women go through depression during their life, and depressive symptoms have been considered a relevant emergent, non-traditional risk factor for CVD in this part of the general population. Underlying mechanisms explaining the link between depression and CVD may range from behavioral to biological risk factors, including sympathetic nervous system hyperactivity and impairment in hypothalamic-pituitary-adrenal function. However, the neuroendocrine-driven background could only partially explain the differences mentioned above for chronic systemic inflammation, altered hemostasis and modulation of cardiac autonomic control. In addition, some evidence also suggests the existence of gender-specific differences in biological responses to mental stress. Given these premises, we here summarize the current knowledge about depression and CVD relationship in women, highlighting the sex differences in physiopathology, clinical presentation and treatments

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care(1) or hospitalization(2-4) after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease. © 2022, The Author(s)

An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

SARS-CoV-2 susceptibility and COVID-19 disease severity are associated with genetic variants affecting gene expression in a variety of tissues

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

People with problematic access to health care. A survey of their perceived state of health.

openIn Italia sono presenti 5,2 milioni di stranieri residenti. La fondazione Iniziative e Studi sulla Multietnicità (ISMU) stima in 520mila persone la presenza in Italia di stranieri irregolari. Sono persone senza dimora o che vivono in case occupate, lavoratori provenienti dall’Unione Europea ma con permesso di soggiorno scaduto, bambini figli di immigrati irregolari. Molte di queste persone hanno diritto ad accedere solo a cure ritenute urgenti ed essenziali, a meno che non riescano ad iscriversi al SSN o paghino un'assicurazione sanitaria. Tante terapie, tanti esami che noi diamo per scontati per queste persone non sono accessibili. Scopi: Misurare lo stato di salute percepito dalle persone partecipanti allo studio. Valutare l’accesso ai servizi sanitari: viene condotta un’analisi dettagliata per comprendere le principali barriere che le persone con un accesso problematico alle cure devono affrontare quando si manifesta un problema di salute. Analizzare le disparità nella salute: si valuta se vi sono differenze significative nello stato di salute percepito tra le persone con accesso problematico alle cure e quelle che hanno un accesso più agevole. Raccogliere dati qualitativi: vengono raccolti dati attraverso le interviste per ottenere una comprensione più approfondita delle esperienze e delle percezioni delle persone coinvolte. Studio osservazionale/descrittivo. Il campione è composto da 36 persone. Per raccogliere i dati riferiti dagli intervistati sono stati uniti due strumenti. Questionario Short Form Health Survey (SF-36) e una serie di domande somministrate insieme al questionario che indagavano la situazione sociale dei pazienti, la presenza di documenti, la conoscenza delle strutture d’aiuto del territorio etc. Per rendere più fluida e comprensibile l’interpretazione dei dati la scala di valutazione di ogni item viene suddivisa in base al punteggio ottenuto: da 0 a 25 stato di salute percepita molto scarsa, da 26 a 50 stato di salute percepita scarsa, da 51 a 75 stato di salute percepita sufficiente, da 76 a 100 stato di salute percepita buona. Analizzando i questionari si nota come la media di ogni item dei questionari SF-36 dei pazienti sia bassa, inferiore al 60. Escludendo uno degli item, tutte le medie si assestano sotto i 50 punti, definendo la loro percezione della salute come “Scarsa” e “Molto scarsa”. Le medie dei questionari per il gruppo di controllo invece sono considerevolmente più alte. Inoltre, le risposte alla seconda parte delle domande hanno evidenziato come il numero di accessi al Pronto Soccorso dei pazienti intervistati sia molto alto, come molti di loro non siano sempre in grado di accedere alle cure che vengono loro prescritte, come molte di queste persone vivano in condizioni che aumentano il rischio di contrarre o cronicizzare alcune malattie. In conclusione, la ricerca ha affrontato un tema di grande rilevanza nell'ambito della sanità pubblica: l'accesso problematico alle cure e il suo impatto sullo stato di salute percepito dalle persone. I risultati di questa indagine hanno confermato l'esistenza di una significativa correlazione tra un accesso problematico alle cure e uno stato di salute percepito negativamente. Le persone che hanno sperimentato difficoltà nell'ottenere l'assistenza medica necessaria hanno manifestato una maggiore insoddisfazione riguardo al proprio stato di salute. Questo legame tra accesso alle cure e percezione dello stato di salute suggerisce che le barriere all'accesso ai servizi sanitari hanno un impatto diretto sulla qualità della vita delle persone. La consapevolezza di queste problematiche è fondamentale per gli operatori sanitari, i responsabili politici e tutti gli attori coinvolti nel settore sanitario al fine di sviluppare strategie efficaci per migliorare l'accessibilità e la qualità delle cure. Rimangono comunque molte sfide aperte e opportunità di ulteriori studi in questo campo